Triple-negative breast cancer (TNBC) accounts for 10-15% of all newly diagnosed breast cancer and carries an increased risk of distant metastasis and death from breast cancer compared to other breast cancer subtypes. Despite efforts to develop effective treatment strategies, patients with metastatic TNBC have a median overall survival of around 13 months. This disease represents an area of unmet need in breast cancer treatment. TNBC is associated with a high nuclear grade, sensitivity to anti-mitotic agents, and dependence on angiogenesis. The Aurora kinases are a family of serine-threonine kinases integral to mitotic cell division and are emerging therapeutic anticancer targets. ENMD-2076 is a novel, orally bioavailable, Aurora and angiogenic kinase inhibitor that has antitumor activity in preclinical models of TNBC. This proposal aims to complete a single-arm, dual institution, two-stage phase II clinical trial of ENMD-2076 in patients with advanced or metastatic, previously treated TNBC. This clinical trial will enroll approximately 35 patients at the University of Colorado Cancer Center (UCCC) and the Indiana University (IU). The objectives of this study are to determine the efficacy of this agent in the treatment of advanced TNBC, including pharmacokinetic and pharmacodynamic investigations. This study will include the performance of serial tumor biopsies, pre-treatment and two weeks post-treatment, for pharmacodynamic studies including modulation of the Aurora kinases. A secondary aim of this study is to explore genomic biomarkers predictive of clinical response to ENMD-2076 in this patient population. Studies are ongoing at the UCCC with ENMD-2076 in preclinical models of TNBC to identify classifiers predictive of response which include alterations in p53 signaling and up- and down-regulated cellular pathways which can be assessed by RT- PCR techniques. The overall goal of this proposal is to develop a novel and effective therapy for advanced TNBC, including the investigation of unique biomarker selection strategies which represents a major area of unmet need in human cancer care.